Effect of Psychological and Medication Therapies for Insomnia on Daytime Functions

Key Points Question Which first-stage treatment is optimal for improving daytime functions among patients with insomnia, and which second-stage treatment offers the best added value for patients whose insomnia has not remitted? Findings In a randomized clinical trial of 211 adults with insomnia disorder, first-stage treatment with behavioral therapy (BT) or zolpidem produced significant improvements for various daytime outcomes, including depressive symptoms, fatigue, functional impairments, and mental health, that were no different between groups. Adding a second-stage therapy offered an added value for further improving daytime functions with immediate and delayed effects observed for treatment sequences starting with zolpidem and BT, respectively. Meaning These findings support the comparable efficacy between sequential treatments starting with BT and zolpidem for addressing the daytime consequences of insomnia.

syndromes 54 , breast cancer 55 , fibromyalgia 56 , mixed medical disorders 57 , alcoholism 58 , and depression 59,60 .Previous findings also suggest that these therapies lead to improvements in mood status, enhanced likelihood of depression remission, and reductions in other disease-specific symptoms among CMI patients 55,56,59,61,62 .Thus, the psychological/behavioral therapies hold promise for CMI patients as well as for those with PI.WHAT SHOULD BE OUR FIRST STAGE INSOMNIA THERAPY AND WHAT SHOULD WE DO WHEN THAT FAILS?Deciding whether to use pharmacological or psychological/behavioral insomnia therapy in general or with specific patients is difficult, since both forms of treatment have their limitations.Medications usually produce rapid improvements, are widely available, and generally well tolerated, but adverse effects including residual daytime sedation, reduced motor coordination, cognitive impairment, tolerance, and rebound effects may complicate their use [63][64][65] , [66][67][68] .Furthermore, there are no data documenting enduring benefits of these agents after their use is discontinued.In contrast, the psychological/behavioral insomnia therapies have minimal side effects, are preferred by many patients, and typically result in enduring sleep improvements long after termination of acute treatment 48,51 .However, these therapies require more extensive provider contact and have a slower rate of therapeutic action than do medications 69,70 .In addition, they are less widely available than BzRAs despite recent efforts to provide their wider dissemination through abbreviated therapy protocols 71,72 , self-help interventions 73 , and the training of non-traditional providers 74 .
Whereas the relative value of BzRA and psychological/behavioral therapies largely depends upon their comparative efficacies and safeties, there have been few head-to-head comparisons of these treatments.One recent trial 75 , which compared CBT with the BzRA, zopiclone, over a 6-week acute treatment phase and subsequent six-month follow-up, showed CBT produced significantly better short-and longer-term improvements on objective (PSG) indices but not on subjective (sleep diary) measures.A few other studies 69,76, 77 that compared a single-agent BzRA therapy, CBT, and combined BzRA/CBT therapy showed little difference in short-term outcomes, but superior longer-term outcomes with CBT compared to BzRA and combined treatment.In contrast, a recently published trial showed a sequential treatment strategy that commenced with 6 weeks of combined CBT/BzRA therapy followed by an extended six months of CBT alone proved superior to continued long-term combined therapy or CBT provided in the absence of any medication 2 .However, these studies are limited by their small sample sizes, use of fixed-dose/fixed-agent pharmacotherapy strategies that do not represent standard clinical practice, and/or their exclusive focus on PI patients.Hence, these findings provide very limited guidance for deciding upon the optimal first-stage insomnia therapy in general and specifically for the prominent and challenging subgroup of CMI patients with psychiatric illnesses.
Further complicating matters are a number of additional oversights in the insomnia treatment literature that limit its usefulness for guiding clinical practice.First, most previous treatment studies have focused on changes in individual quantitative sleep measures (e.g.sleep onset latency, total sleep time) to gauge treatment outcomes.These indices are important, but they miss other relevant symptoms such as daytime fatigue, cognitive efficiency, and overall sleep satisfaction which patients regard as particularly important and clinicians use to assess global improvement [78][79][80][81] .Moreover, few studies have assessed treatments using validated measures of insomnia remission, the outcome most relevant to clinical practice.Secondly, it remains unclear how well CMI patients respond to the standard doses/protocols of insomnia therapies established for PI patients.Emerging evidence 82 suggests CMI patients demonstrate greater adherence difficulties to CBT than do PI patients, and our own data (see preliminary studies) indicate CMI patients show a less robust CBT response than do PI sufferers when global insomnia syndrome measures are considered.Likewise, recent studies 83 using the Insomnia Severity Index 84 to assess the efficacy of the BzRA, eszopiclone, show large treatment effect sizes = 0.87 for PI patients but smaller effect sizes = 0.46 and 0.48 in patients with comorbid generalized anxiety disorders and major depression respectively.CMI patients, thus, may have a more blunted response to first-stage insomnia therapy than do PI patients regardless of the specific modality they receive.Finally, extant data shows a large proportion of patients fail to remit with first-stage therapy and are, thus, left with residual insomnia symptoms. 51In such situations, switching from one therapy to another, on a trial-error basis, is common clinical practice.Yet, no studies have addressed such important questions as: (1) Which second-stage treatment offers the best hope for insomnia remission, once a reasonable course of a psychological or medication first-stage therapy fails to achieve this endpoint?and (2) Do the optimal firststage-to-second-stage treatment sequences differ for those with CMI and PI?
When selecting first stage therapies to test, we chose two distinctive treatment modalities that are well supported, relatively easy to administer, and frequently used.One is the medication, zolpidem, which has well established efficacy and is now the most often prescribed BzRA for insomnia 43 .Our alternate first line therapy will be a behavioral therapy (BT) comprised of stimulus control, sleep restriction, and sleep hygiene education.Although multi-component CBT may represent the psychological treatment of choice, we have chosen to employ only its core behavioral elements so as to make this therapy easy to deliver and ultimately more transferable to clinical settings.BT and Zolpidem will also serve as second-stage therapies so that we can assess effects of switching from one type of sleep-focused therapy to another (e.g., BzRA→BT) We chose trazodone as an alternate second-stage pharmacotherapy since this medication has enjoyed wide off-label use as a sleep aid over the past several decades, a different mechanism of action than BzRAs, and proven efficacious among CMI patients with mood disorders 43,46,47 .Finally we chose to test the Cognitive Therapy (CT) component of CBT as an independent second-stage treatment.CT seems reasonable to choose as a second stage therapy since it is time consuming to deliver and not essential for all insomnia patients.Yet, CT is designed to target critical cognitive perpetuating mechanisms for insomnia (worries, self-monitoring, negative automatic thoughts), some of which may be shared with other psychiatric disorders (e.g., anxiety and depression).These cognitive factors are not specifically addressed by BT.Thus, CT's impact could be broader and improve mood and sleep, a very desirable outcome among patients with comorbid psychiatric disorders.

(b) Innovation:
The proposed project entails a dual-site, open-label trial examining sequential treatment with well-supported and commonly used therapies to asses their relative efficacy and safety.This project has the following innovative features designed to advance understanding of the treatment needs of insomnia sufferers, particularly those with treatment-resistant psychiatric illnesses: (1) Enrollment of participants with broadly-defined chronic insomnia disorder, with and without psychiatric comorbidity; (2) use of the clinically-relevant primary outcome, insomnia remission, rather than the traditional, less relevant quantitative parameters (e.g., sleep time, sleep onset latency); (3) use of a sequential treatment design that tests various first-stage-to-second-stage treatment sequences; (4) flexible medication dosing, rather than a fixed-agent/fixed dose design; and (5) plans to systematically collect AE data for both psychological and medication therapies so that the relative safety of the two approaches can be examined.This project should provide new and relevant information that contributes to the development of clinical guidelines for CMI and PI management, guidelines which are critically lacking 85 .
(c) Approach: c.1 Study Design and Rationale.Adults with chronic insomnia (n = 320) will be randomly assigned to zolpidem therapy (MED; n = 160) or behavioral therapy (BT; n = 160), stratified by gender, age (< 55 years vs. ≥ 55 years), and insomnia subtype (primary-PI vs. comorbid-CMI).We expect roughly 50% of our sample will be ≥ 55 years old, about 60% will be women, and we will recruit 60% with insomnia comorbid to a mental disorder.We will monitor other variables (e.g., prior usage of hypnotic medications) that might be related to treatment response and, if necessary, control for these in statistical analyses.After completing the initial 6-week treatment phase, treatment remitters will remain on maintenance therapy.Non-remitters will be encouraged to accept randomization to a second-stage alternate therapy provided over the next 6 weeks.Participants treated with BT initially will receive another psychological treatment, CT, or a medication therapy (zolpidem).Those treated with medication (zolpidem) initially will be switched to BT or to a different medication (trazodone).Measurements will be taken at baseline, at the end of first-and second-stage therapies (i.e., weeks 6 and 12), and at follow-ups conducted 3, 6, 9, and 12 months after the week 12 assessment.
This study design derives from our primary aims: (1) to compare outcomes of BT and zolpidem when provided as first-stage therapies for insomnia patients with/without psychiatric comorbidity and (2) to assess the value-added of switching strategies for those not achieving remission with first-stage therapy.The BzRA, zolpidem is included because it is readily available and the most widely used pharmacotherapy for insomnia.BT was chosen for comparison because it is an effective, pragmatic, and safe treatment option that is preferred CBT+Med / CBT+Taper by many patients.Evidence suggests both BZRAs and BT produce a treatment response in roughly 60%-70% of patients, although only about 40% of all patients achieve remission.The second-stage treatments will show whether added efforts involving changing therapy within a broad treatment class (psychological or medication), or switching to an alternate mode of therapy will bring more patients into remission.Several alternative conditions were considered when planning this study.For instance, although CBT is becoming the standard approach to treating insomnia, we decided to introduce its two main therapeutic components (BT and CT) in a sequential fashion rather than as a treatment package.First, there is much stronger evidence supporting BT than CT; in addition, BT is easier to implement than CT (by non-specialists), thus enhancing its transferability to clinical practice.We also considered using a combined treatment involving concurrent use of medication and CBT but decided against this option because it is rarely available as a firststage therapy and because the evidence suggest that combined CBT/MED therapy is not necessarily optimal, when long-term outcomes are considered.Our study design provides a unique opportunity to test the impact of sequential rather than concurrent therapies.We also considered including a placebo-control condition but decided not to do so because our research questions are not about documenting treatment efficacy relative to placebo; such data are already available.Rather, our main questions concern the comparative efficacy of firststage psychological and pharmacological therapies and their optimal sequencing as second-stage therapies for CMI and PI.In the end, we believe the design chosen is the most appropriate to answer our specific research questions, while offering the best compromise in terms of feasibility, cost, and statistical power.
c.2 Preliminary Studies.The preliminary studies (a) show the PIs' experience and leadership in conducting RCTs of insomnia therapies, (b) provide rationale for the therapies chosen and study hypotheses and, (c) support the feasibility of the project proposed (See Appendix 1 for overall collaborative plan).
CBT and Medication for Persistent Insomnia: Short-Term and Maintenance Treatment Effects. 2 Dr. Morin's group conducted this study to evaluate the short-term effects of CBT, alone and combined with medication, and to compare effects of varied treatment sequencing strategies on long-term outcomes.A total of 160 chronic insomnia patients (61% women; mean age of 50.3 yrs) were randomized to CBT (n = 80) or CBT plus nightly 10 mg zolpidem (n = 80) for an initial 6-week treatment.After completing this treatment, they were randomized again for an extended 6-month treatment.Patients initially treated with CBT alone continued with extended individualized CBT or received no additional treatment; those who received combined treatment initially continued with an extended treatment consisting of CBT plus intermittent medication (10 pills per month) or CBT alone.Of the 160 patients enrolled, 148 completed acute treatment, 141 completed extended treatment, and 127 patients were available at 6-month and 125 at 12-month FUs (overall attrition rate of 22% over a 1-year period).Outcomes were examined in terms of treatment response (change on the Insomnia Severity Index (ISI) > 7) and remission (ISI value < 8).Although the proportion of treatment responders was comparable with CBT alone (60%) and CBT plus medication (61%) at the end of acute treatment, different trajectories of change emerged over the following 6 months depending on whether therapy was provided.More patients responded with maintenance CBT than without (63% vs. 55%).Also, patients treated with combined therapy initially did slightly better during maintenance therapy when medication was stopped compared to intermittent usage (74% vs. 70% responders), and this trend became significant at the 6-month follow-up (81% vs. 65%).A similar pattern emerged regarding remission.Remission rates were 39% (CBT alone) and 44% (CBT + medication) after acute therapy, and there was no significant difference after extended therapy between CBT and no additional treatment or between CBT alone and CBT plus intermittent medication.At the 6-month follow up, however, remission rates were significantly higher among those who had received maintenance CBT than among those who did not (46% vs. 40%) and among those who discontinued medication versus those who continued with intermittent medication (68% vs. 42%).These findings, while preliminary, have implications for the current proposal.First, CBT + medication may not provide a strong advantage over CBT alone, at least on acute outcome.Second, the addition of a second-stage alternate psychological therapy may enhance long-term remission rates.Thirdly, when combined therapy is used as first-stage therapy, long-term remission rates may be enhanced by tapering medication while patients are still receiving CBT.Although informative, these conclusions remain tentative because the findings were based on a limited sample obtained at only one site and only patients with primary insomnia were enrolled.In addition, the study made no comparison between CBT alone and medication alone.Moreover, the randomization to secondstage therapy did not consider initial treatment response, a factor that should guide second-stage therapy.
Instability of sleep and bedtime arousal in CMI and PI patients 86 .This study conducted by Dr. Edinger's group, examined patterns of sleep disturbance and bedtime arousal in individuals with PI and CMI related to a mental disorder.The study included 187 insomnia sufferers (126 women, M Age = 47 years) assigned either PI (n = 126) or CMI (n = 61) diagnoses by 6 sleep specialists at one or the other of two collaborating medical centers.Results showed CMI patients displayed significantly longer SOL, on average, and significantly more instability across nights in their TST (i.e., larger changes) than did PI patients.CMI patients exhibited higher levels of somatic, cognitive and emotional arousal as well as more instability on nightly ratings of emotional arousal.Correlations revealed a significant relationship between pre-sleep arousal and SOL in the PI group (r values from 0.26 to 0.34), whereas corresponding correlations between all sleep and bedtime arousal measures were non significant in the CMI group (r values < 0.14).Despite greater levels of arousal and longer SOLs in the CMI group, they showed less correspondence between sleep and arousal than did the PI group.The findings imply these two groups have different perpetuating mechanisms and treatment targets/needs.
Psychiatric comorbidity as a moderator of CBT response 1 .Dr. Edinger's group also conducted this study to determine if PI and CMI patients derive comparable benefits from CBT. Participants (70 men, 11 women; M Age = 54.2 ±13.8 yrs.) met criteria for PI (n = 40) or CMI (n = 41).Most of the CMI patients met criteria for a depressive disorder (MDD or dysthymia; n = 16) or combat-related Posttraumatic Stress Disorder (n = 18).Patients were randomly assigned to either CBT or a sleep hygiene control therapy (SH) entailing lifestyle (e.g., limit caffeine) and environmental manipulations (e.g., keep bedroom dark) to enhance sleep.Each treatment consisted of 4 biweekly, 30-to 60-minute individual sessions with a study therapist.
Comparisons of these groups using traditional quantitative sleep parameters (e.g., TST, SOL) suggested no consistent differences in their relative CBT responsiveness.However when more global measures of the overall insomnia syndrome were considered, the PI group was more responsive to CBT than the CMI group.For example, on the Insomnia Symptom Questionnaire, an instrument designed to assess changes in both daytime and nighttime symptoms, CBT-treated PI patients displayed a much larger treatment effect size (.87) than did CBT-treated CMI patients (.34).Moreover, 75.8% of the CBT-treated PI patients achieved normal scores on the Pittsburgh Sleep Quality Index by the end of treatment, compared to only 19% of the CBT-treated CMI patients (see figure).These two instruments most closely approximate the global insomnia disorder assessment provided by the Insomnia Severity Index, which will serve as the primary outcome for the project proposed.Thus, we believe these data suggest BT-treated CMI patients will have a lower ISI measured remission rate following first-stage treatment than will BT-treated PI patients.c.3 Subjects Selection Criteria.We will recruit adults (aged 21 and older) with chronic insomnia from the community and from outpatient medical and mental health clinics.Inclusion criteria will be broad to obtain results widely generalizable to the insomnia patient population commonly seen in practice.The inclusion criteria are: (a) a complaint of persistent (i.e., > 1 month) difficulties initiating or maintaining sleep despite adequate opportunity for sleep; (b) a sleep onset latency or wake time after sleep onset > 30 minutes 3 or more nights per week during two weeks sleep diary monitoring; (c) an Insomnia Severity Index (ISI) score > 10 indicating at least "mild" insomnia; and (d) a score ≥ 2 on either the interference or distress item of the screening ISI, indicating the insomnia causes significant distress or impairment in social, occupational, or other areas of functioning.These criteria represent those provided in the DSM-IV-TR 87 , Research Diagnostic Criteria 3 and the International Classification of Sleep Disorders 4 , and will ensure a sample with clinically relevant insomnia.Exclusion criteria will be minimal to retain a broadly representative sample that includes patients with primary and insomnia comorbid to a psychiatric disorder.Likewise, individuals with a comorbid medical condition will be excluded only if the medical condition is life-threatening or would contra-indicate using study medications.Exclusion criteria are (a) an untreated psychiatric disorder (e.g., major depression) as these conditions have specific treatments and it would be inappropriate not to offer those treatments; (b) a lifetime diagnosis of any psychotic or bipolar disorder as sleep restriction and medications for insomnia may precipitate mania and hallucinations; (c) an imminent risk for suicide; (d) alcohol or drug abuse within the past year, since BzRAs are cross-tolerant with alcohol; (e) terminal or progressive physical illness (e.g., cancer, COPD), or neurological degenerative disease (e.g., dementia); (f) current use of medications known to cause insomnia (e.g., steroids); (g) sleep apnea (apnea/hypopnea index > 15), restless legs syndrome, periodic limb movement during sleep (PLMS with arousal > 15 per hour), or a circadian rhythm sleep disorder (e.g., advanced sleep phase syndrome); (h) habitual bedtimes later than 2:00 AM or rising times later than 10:00 AM; (i) consuming > 2 alcoholic beverages per day on a regular basis.
Individuals using sleep-aids (prescribed or over-the-counter) will be included if they are willing and able to discontinue medications at least 2 weeks before baseline assessment.Participants using alcohol as a sleep aid or alcohol after 7:00pm on a regular basis will be required to discontinue this practice at least two weeks prior to baseline assessment.Individuals using psychotropic medications (e.g., anxiolytics, antidepressants) will not be automatically excluded from the study.Those on stable dosages (for at least three months) of SSRI or SNRI medications and who show at least partial remission (via SCID) from their mood or anxiety disorder will be accepted in the study if they meet the selection criteria above.Patients using TCAs, MAOIs, or atypical antidepressants will be excluded even if in remission as the effects of these medications on sleep might confound interpretation of the findings.We will impose similar standards for those with MDD, dysthymia, panic disorder, phobia, and GAD.We realize that some decisions about enrollment may not always be easy to make, but we will rely on all available data and a consensus approach to guide our clinical decision making process.
Recruitment/Participant Flow.Participants will be recruited at two sites (Duke and Laval Universities), each of which has an active insomnia research program with proven infrastructures for clinical trials.We will recruit participants through media advertisements, flyers distributed in outpatient clinics, and letters to primary care physicians and mental-health clinicians.We have ongoing referrals from these sources at each study site, including many with difficult forms of insomnia comorbid with psychiatric conditions.We recognize that CMI patients are relatively more prevalent than PI sufferers, and our study aims are designed to determine the optimal treatment(s) for such individuals.We will use a targeted recruitment approach so that roughly 60% (n = 192) of the 320 patients enrolled will have CMI.Given our usual mix of clinic and research referrals, we are confident the CMI patients enrolled will comprise a mixture of anxiety disorders (GAD, panic, phobia, PTSD) as well as mood disorders (e.g.dysthymia) other than major depression so our study results should add to and compliment ongoing NIMH funded trials focused exclusively on CMI in MDD.Based on our previous trials, we expect 400-500 individuals to inquire about the study at each site during the 48 months of enrollment.Approximately 40%-50% should meet study criteria so 3-4 participants are enrolled monthly at each site.We expect that attrition will be limited since study participants will be provided free ongoing treatment and financial incentives.Recent experiences with trials involving behavioral and pharmacological insomnia therapies at both sites have shown attrition rates in the 10% to 20% range.Should attrition be higher than expected, we are prepared to enroll 10-20 additional subjects per site in this trial to maintain adequate statistical power.c.4 Sleep-Wake Monitoring Polysomnography.Study participants will undergo standard nocturnal polysomnographic (PSG) monitoring for screening and outcome assessment.The initial PSG will serve to detect sleep disorders that would lead to exclusion (see selection criteria, c.3) and to provide an initial baseline night for those enrolled.Patients who meet criteria will complete additional PSG recordings at various times to assess outcomes (see Table C.5). PSG monitoring will be conducted in the sleep laboratories according to standard procedures with regard to montage and sampling rate (256 Hz), and bedtimes and rising times.Patients randomized to medication conditions will take their study medication (zolpidem or trazodone) at the time of sleep studies.Participants will undergo PSG on their usual dosages of allowed psychotropics (e.g., SSRI) and other medications (e.g., antihypertensive agents) since these medicated individuals will have active insomnia despite using medications.PSG recordings will be scored, blind to treatment assignment, in 30-second epochs using standard scoring criteria 88 for sleep staging and characterization of sleep-associated events (e.g., apneas).The initial screening/baseline PSG will be scored at the site where it is recorded to ensure a timely decision regarding study inclusion.All remaining PSG records will be scored centrally at the Duke site by trained technologists under the supervision of Dr. Krystal, an experienced, board-certified polysomnographer.
IVRS Sleep Diary System.Subjective estimates of sleep and wake times will be obtained daily using an interactive telephone voice response system (IVRS).Participants will phone the IVRS system each morning and report the following information about their previous night's sleep: bedtime, sleep onset latency, number and length of nocturnal awakenings, time of final waking, rising time, ratings of sleep quality and restedness upon arising.Additional questions will query caffeine, alcohol, and sleep medication use.The IVRS program will automatically record a time and date stamp to verify when the data were entered.IVRS sleep diaries will be obtained for 2-weeks at baseline and at each subsequent assessment period.c.5 Measures Screening Instruments.Two structured interviews will be used.The Duke Structured Interview for Sleep Disorders (DSISD; Appendix II) 89 , is an instrument developed by Dr. Edinger and colleagues to assist in ascertaining DSM-IV-TR 87 and International Classification of Sleep Disorders (ICSD-2) 4, 90, 91 sleep disorder diagnoses.This instrument has acceptable reliability and discriminant validity 1 .In addition, the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) 92 will be used to classify enrollees as having primary or comorbid insomnia and to identify study candidates with disorders (e.g., Bipolar Disorder) leading to exclusion.In addition to widespread use in clinical research, the SCID is supported by extensive reliability and validity data.All interviews will be audio taped and reliability checks will be conducted on 15% of them.We will administer the Folstein Mini-Mental Status Exam (MMSE) 93 to exclude those with cognitive deficits (MMSE score < 27) that make them unable to give informed consent or fully participate in an interactive treatment.
Outcome Measures.The primary outcome metric will be the proportion of individuals achieving remission by producing scores < 7 the Insomnia Severity Index (ISI) 32 .The ISI is a 7-item self-report questionnaire that provides a global measure of perceived insomnia severity based on several indicators (e.g., difficulty falling or staying asleep, satisfaction with sleep, degree of impairment with daytime functioning).The total score ranges from 0-28: 0-7 (no clinical insomnia), 8-14 (sub threshold insomnia), 15-21 (insomnia of moderate severity), and 22-28 (severe insomnia).The ISI has been validated 84 and has proven sensitive to therapeutic changes in several treatment studies of insomnia 69,94 .
We will track a number of secondary outcomes.Among these are measures of sleep/insomnia status including: sleep onset latency (SOL), wake time after sleep onset (WASO), total sleep time (TST), sleep efficiency (SE) taken from both sleep diaries and PSG.Diary ratings of sleep quality and feeling rested upon arising will also be obtained.Patients will complete the Pittsburgh Sleep Quality Index (PSQI) 95 at various time points to reflect their changes in overall sleep quality.The PSQI is widely used in clinical research and has validated cut-off scores to optimize sensitivity and specificity as a measure of insomnia 96,97 A clinical global improvement (CGI) 98 rating will be completed by a blinded rater to provide a measure of insomnia severity and intervention effects.Despite some limitations about reliability and validity 99 , the CGI will serve as a useful comparator with other insomnia trials.Finally the blinded rater will interview participants at the conclusion of their study involvement using the DSISD to determine whether they continue to meet RDC for insomnia.
To reflect treatment-related changes in daytime function, participants will complete the Multidimentional Fatigue Inventory (MFI) 100 , the SF-36 Health Survey (SF-36) 101 and the insomnia adaptation of the Sheehan Disability Scale (SDS-I) 102 .The well-validated 100 20-item MFI assesses several dimensions of fatigue (e.g., physical, mental) and has been used in studies of chronic pain 103 , cancer 104 and depression 105 .The SF-36 is a quality of life measure that comprises eight scales (e.g., Physical functioning, Bodily Pain, Vitality) and 2 summary measures (Physical Health and Mental Health) 106,107 .The SDS-I measures impairment in three major areas of functioning: work, social life/leisure activities, and home life/family responsibilities.It has been widely used in clinical trials for anxiety and depressive disorders and, more recently, in insomnia trials 108 .
Changes in mood status will be assessed by including such well-validated and widely used measures as the Beck Depression Inventory-II (BDI-II) 109 , State-Trait Anxiety Inventory (STAI) 110 and the Beck Anxiety Inventory (BAI) 111 .These instruments have well-established psychometric properties and have been used extensively in clinical research including studies of insomnia 112 .
Adverse events (AE) monitoring will be achieved by using the Systematic Assessment for Treatment Emergent Events (SAFTEE) a reliable and valid instrument for assessing AEs related to study treatments. 113,114 Fnally, we will use an amended version of the Therapy Evaluation Questionnaire (appendix III) to assess treatment credibility, acceptability and patient satisfaction 115 .c.6 Procedures Study candidates will undergo a multi-level screening.After an initial telephone screening, they will